Hunter syndrome (MPS II) is an inherited disease that belongs to a group of metabolic disorders known as the mucopolysaccharidoses (MPS syndromes). These rare disorders are all caused by deficiencies in lysosomal enzymes, essential for breaking down various substances in the body. This leads to accumulation of the substance that would normally be degraded by the enzyme, resulting in tissue and organ damage. Hunter syndrome was described for the first time in 1917, by the Canadian Professor Charles Hunter.

In total, there are seven known MPS syndromes. They are either named after the physician who first described them or after the deficient enzyme. They have also been labelled numerically. It is becoming increasingly common to use numeric labelling, such as MPS II, or a name that describes the deficient enzyme, such as iduronate sulfatase deficiency.

The cause of Hunter syndrome is a mutation in a gene which controls the production of (codes for) the enzyme iduronate sulfatase. This gene, known as IDS, is located on the long arm of the X chromosome (Xq27-28).

The enzyme iduronate sulfatase contributes to breaking down mucopolysaccharides (also known as glycosaminoglycans). These saccharides, with their long chains of carbohydrate units, are components of various tissues. Breakdown of the mucopolysaccharides normally takes place in the cell lysosomes, small units found in all cells except red blood cells. Lysosomes contain enzymes, proteins that contribute to chemical reactions without themselves undergoing any permanent change, and their function is to digest and break down various substances.

Hunter syndrome is characterized by iduronate sulfatase deficiency, which results in the build-up of undigested mucopolysaccharides in the cells. These aggregations damage various tissues and organs in the body.

The inheritance pattern of Hunter syndrome is X-linked recessive. An X-linked recessive inheritance pattern is caused by a mutated gene located on the X chromosome, which is one of the chromosomes determining sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50% risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene.

There are isolated case reports of women with Hunter syndrome.

Hunter syndrome may also be caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and a man with this mutation risks passing on the mutated gene to his children.

Hunter Syndrome is usually described as occurring in two forms, one mild that is non-neurological and one severe that is neurological, the latter being more common. The disorder is referred to as severe if symptoms include cognitive impairment. The two forms of Hunter syndrome represent the extremes of what is really a spectrum of symptoms, with considerable variations even within a single family.

Symptoms associated with severe Hunter syndrome

In the severe form of Hunter syndrome the brain, heart, joints, skeleton, respiratory tract, liver, eyes and ears are all affected by the build-up of mucopolysaccharides. The clinical features of the disorder resemble those of Hurler syndrome, another of the MPS syndromes, but Hunter syndrome progresses more slowly and the skeleton is not affected to the same extent. These boys are born healthy and develop normally until they are between two and four years old, when symptoms begin to appear.

The syndrome is associated with typical facial features, including a flattened bridge of the nose, broad lips, enlarged tongue, prominent eyebrows, thick hair and excess body hair, although all boys with the syndrome do not develop these characteristics. Other characteristic features include a large head with a prominent forehead, enlarged abdomen, a characteristic gait and typical arm posture.

Mucopolysaccharide aggregation in the brain affects cognitive development, and in the severe form the boys regress so that they gradually lose previously acquired skills. However, there is considerable variation in the development of cognitive skills.

Mucopolysaccharide deposition in the meninges (the membranes that cover the brain and spinal cord) prevents normal drainage of cerebrospinal fluid, and may lead to the development of hydrocephalus.

The heart may be affected, but not necessarily until late in life. Both the heart musculature and the heart valves may become weakened and enlarged by accumulated mucopolysaccharides (cardiomyopathy). The coronary arteries may also become obstructed.

Recurrent upper respiratory tract infections, pulmonary infections, and ear infections are a major problem in Hunter syndrome. Stiff lungs and recurrent pulmonary infections may increase the risk of right heart enlargement (cor pulmonale). Many of these boys have breathing problems related to sleep, and it is very common to have brief breathing pauses during sleep (sleep apnoea).

The abdomen protrudes owing to enlarged liver and spleen in combination with weak abdominal musculature, and inguinal (groin) or umbilical hernias are common.

All joints may be affected by the build-up of mucopolysaccharides, manifesting as stiffness. This may lead to contractures in the knees, hips, elbows, shoulders and finger joints. The feet often have high arches. Claw hands are another symptom that may affect fine motor skills. Carpal tunnel syndrome (see below) is very common. The vertebrae may be underdeveloped, leading to abnormal curvature of the spine (kyphosis). Growth is inhibited and final stature will be below average.

The teeth are small and widely spaced. Mucopolysaccharide deposits in the gums may cause problems, both when the milk teeth and the permanent teeth are supposed to erupt.

Impaired hearing may be caused by auditory nerve damage, or by fluids collecting behind the eardrum as a consequence of recurrent ear infections. Visual impairment is rare in Hunter syndrome, but may occur. Loss of vision may be a consequence of deposits forming in the retina. Without enzyme therapy (see under “Treatment”), life expectancy in the most severe form of Hunter syndrome is shortened, and although there is considerable variation among individuals, these boys rarely live beyond their teens.

Symptoms of the mild/non-neurological form of Hunter syndrome

In the mild form of Hunter syndrome, cognitive development is normal. However, the designation “mild” may be misleading as key organs and tissues in the body can still be significantly affected. Conversely, apart from cognitive impairment boys with the severe form sometimes only have minor symptoms. The mild form progresses at a slower pace than the severe, neurological form, but there is considerable individual variation. The facial features are the same as in the severe form. Most of these boys have impaired hearing, but vision is rarely affected.

Carpal tunnel syndrome is caused by entrapment of a nerve in the wrist, resulting in pain and numbness. In severe cases, some of the thumb muscles may atrophy. In the MPS syndromes, it is the abnormal thickening of connective tissue that puts pressure on the nerve in the wrist.

Growth is also affected, and final stature is usually at most 150-160 cm.

As in the severe form, the heart may be affected. There is a risk of arrhythmias, weakened heart musculature, and obstructed coronary arteries. High blood pressure is a common complication.

This form of the syndrome is also associated with recurrent respiratory and lung infections.

With increasing age there is a considerable risk that the vertebral column will be compressed by thickened surrounding membranes. It is therefore important to have an MRI (magnetic resonance imaging) of the spinal column if the arms, hands or legs should become weakened, or if symptoms such as spasticity or incontinence should arise.

In the mild, non-neurological form of Hunter syndrome, life expectancy is not necessarily shortened, but heart and lung problems can cause premature death.

MPS syndromes are traced by testing urine for elevated levels of glycosaminoglycans (mucopolysaccharides). Thereafter the exact type of enzyme deficiency is determined in a blood test. The precise diagnosis is confirmed when the blood level of the enzyme iduronate sulfatase is abnormally low, and heparan sulfate and dermatan sulfate concentrations are elevated.

There are no biochemical markers that distinguish the two forms of the syndrome; it is the clinical presentation that determines severity. It is hoped that in the future it will be possible to link specific molecular genetic anomalies to clinical manifestations, thereby enabling a reliable prognosis in each individual case.

It is possible to make a diagnosis based on DNA testing. Deletions (a mutation in which part of a chromosome or sequence of DNA is missing) are more common than point mutations in the severe form.

At the time the diagnosis is made the family should be offered genetic counselling. Carrier diagnosis, prenatal diagnosis and preimplantation genetic diagnosis (PGD) in association with IVF are possible if the mutation in the family has been identified.

There is currently no complete cure for Hunter syndrome. However, enzyme replacement therapy is now available as the deficient enzyme has been produced using recombitant DNA technology, and has been approved for use as a medical drug. The enzyme is administered via intravenous infusion once weekly. This treatment has proven effective for joints and the respiratory tract. It also decreases the size of the liver and improves general health, but as yet it has not been possible to establish any effect on neurological symptoms. International studies are ongoing for follow-up of all treated patients, and for determining the benefits of enzyme replacement therapy in individual organs. It will hopefully be possible to evaluate these studies within the nearest decade. Other interventions aim to prevent complications and ensure the best possible quality of life.

All boys with Hunter syndrome should be treated by a medical team with expertise in the disorder, including specialists in cardiology, pulmonology, neurology, and orthopaedics, as well as an audiologist and an ophthalmologist. The team also offers advice on suitable treatment. It is important that the various specialists cooperate in implementing a coordinated treatment plan. There are recommended European guidelines for follow-up and treatment.

As hearing impairment is common, hearing tests should be carried out regularly. It may be necessary to clear the auditory canal and to insert a small plastic tube (a grommet) in order to drain fluid from behind the eardrum. To facilitate communication, hearing aids should be fitted at a young age.

Hydrocephalus is sometimes a complication of Hunter syndrome. It is treated by surgically inserting a shunt to divert excess fluid from the brain to the abdomen via a tube.

Many boys with Hunter syndrome periodically have gastrointestinal problems, such as diarrhoea, which should be treated through dietary therapy.

Because the airways are narrowed, all individuals with mucopolysaccharidosis syndromes have a risk of complications in association with anaesthesia. Patients with MPS syndromes should therefore be examined by an experienced anaesthetist before planned surgery. This is because narrow airways complicate tracheal intubation (the placement of a tube into the windpipe for breathing assistance during surgical intervention). In many cases a nasal tube may therefore be preferable. Surgical intervention in older children and adolescents should be preceded by an MRI of the cervical spine to reveal the risk for vertebral luxation (dislocation).

Haematopoietic stem cell transplantation (transplantation of blood stem cells), used for treating a number of other enzyme deficiency disorders (such as Hurler syndrome), has not proven effective in halting the progression of Hunter syndrome.

Habilitation

The child and his family require early contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development.

Support and treatment take place within the medical, educational, psychological, social and technical fields. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support. The family may also require help in coordinating different forms of help.

Habilitation focuses on existing needs, may vary over time, and takes place in collaboration with individuals close to the child.

A physiotherapist can provide breathing exercises that are effective for removing phlegm from the lungs, as well as general exercises to improve health. There are many assistive devices that facilitate daily life activities.

Contractures result from thickened, stiff ligaments and muscle tendons around the joints, made rigid by MPS deposits. Physical therapy does not relieve this condition. Contractures are also likely to recur, even after orthopaedic surgery. A physiotherapist will, however, provide advice on suitable exercises for retaining as much joint mobility as possible. Therapeutic foot supports (orthoses) may also be helpful. Stretching exercises that cause pain should be avoided.

If the brain is affected, a speech pathologist and a special education teacher can assist in developing communication skills and stimulating the capacities and interests of these boys. To ensure the best possible quality of life it is important to begin this training early, before the child starts to show signs of weakened cognitive skills. It is important to experiment and collaborate with the child and his family in finding things to do that are inspiring and fun for everyone involved. For example, favourite stories and music can be saved, as can recordings of the child’s own voice.

All teaching must be adapted to the capacities and limitations of the individual. Short-term memory is usually affected first, while long-term memory remains more stable.

Psychological support adapted to age and maturity should be made available continuously through childhood. Even small children need their questions answered.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care, for example, can take the form of a contact family or short-term accommodation outside the home. Special assistance can help the family lead an active life despite the child’s disabilities.

Boys in their late teens and adults require continued medical follow-up and habilitation adapted to their individual needs, usually carried out at a centre for adult habilitation and/or a neurology clinic.

Individuals with the non-neurological form of Hunter syndrome may require educational counselling or help and advice on choosing accommodation.

Paediatricians and paediatric neurologists at district and regional hospitals use laboratory tests to make a diagnosis.

Two Swedish laboratories specialising in metabolic diseases have resources for making clinical chemical diagnoses: The Department of Chemistry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, and the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Solna, SE-171 76 Stockholm.

DNA-based diagnostics is carried out at the Department of Clinical Genetics, The Rudbeck Laboratory, Uppsala University Hospital, SE-751 85, Uppsala, Sweden.

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visit Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Frambu, The Norwegian Resource Centre for Rare Disorders, arranges annual family stays for children and young persons with Hurler/Hunter syndromes and their parents. Swedish families are also invited to participate, but there is currently no agreement between Norway and Sweden that regulates economic compensation for the stay and travel expenses. Information is available from Frambu, The Norwegian Resource Centre for Rare Disorders, Sandbakkveien 18, NO-1404 Siggerud, Norway. Tel: +47 64 85 60 00, fax: +47 64 85 60 99. Email: info@frambu.no, www.frambu.no.

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Intensive research on the MPS syndromes is ongoing around the world. Animal models are used to investigate different treatment possibilities, such as stem cell transplantation, gene therapy, enzyme therapy, and the administration of enzyme directly into spinal fluid. There are also clinical trials on chaperone therapy (chaperones are small molecules that assist in transporting enzyme from the blood into the brain). Data on molecular genetic changes is collected with the purpose of learning more about the correlation between clinical symptoms and specific mutations (genotype-phenotype correlation). Screening methods are evaluated with the aim of facilitating early diagnosis and prompt treatment as well as providing genetic information.

Studies that aim to map genes associated with Hunter syndrome are ongoing at the Department of Medical Genetics at the Uppsala University Biomedical Center, in the form of an international research project led by Associate Professor Marie-Louise Bondesson.

Gene therapy trials are ongoing, but no results have been reported to date.

Newsletter from Ågrenska on the Mucopolysaccharidoses, nr 224 (2003). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

The English Society for Mucopolysaccharide Diseases and the American National MPS Society publish information on the MPS syndromes in English.

Contact

See also

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.